Methotrexate Composition

ABSTRACT

A Methotrexate composition for oral administration is provided comprising a pharmaceutically acceptable salt of Methotrexate and an aqueous carrier agent. The Methotrexate salt is substantially or completely soluble in the aqueous carrier agent, forming an aqueous solution. There is also provided a method of manufacturing a Methotrexate composition for oral administration, comprising mixing a pharmaceutically acceptable salt of Methotrexate with an aqueous carrier agent until the Methotrexate salt is substantially or completely soluble in the carrier agent to form an aqueous solution.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation application of U.S. Ser. No.16/266,305 filed Feb. 4, 2019 (U.S. Pat. No. 10,610,485) which is acontinuation application of U.S. Ser. No. 15/821,242 filed Nov. 22, 2017(U.S. Pat. No. 10,231,927) which is a continuation of U.S. Ser. No.15/019,244 filed Feb. 9, 2016 (U.S. Pat. No. 9,855,215) which is acontinuation of U.S. Ser. No. 13/733,031 filed Jan. 2, 2013 (U.S. Pat.No. 9,259,427) which claims priority to British Patent Application No.1200192.1 filed 6 Jan. 2012, each of which is incorporated herein byreference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Non-applicable

THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT

Non-applicable

REFERENCE TO A “SEQUENCE LISTING”

Non-applicable

BACKGROUND OF THE INVENTION

This invention relates to a Methotrexate composition, a method of usethereof and a method of manufacture.

Methotrexate has the systemic name of(2S)-2-[(4-{[2,4-diaminopteridin-6-yl)methyl](methyl)amino}benzoyl)amino]pentanedioicacid or C₂₀H₂₂N₈O₅. It is used as a folic acid antagonist, in thetreatment of neoplastic disease, such as trophoblastic neoplasms andleukaemia and in the control of severe recalcitrant psoriasis which isnot responsive to other forms of therapy. It is also used to treat awide range of tumours, such as acute leukaemias, Non-Hodgkin's lymphoma,soft tissue and bone sarcomas, solid tumours like breast, lung, head,neck, bladder, cervical, ovarian and testicular cancer, as animmunosuppressant and as an anti-metabolite.

Use of Methotrexate containing compositions for oral administration intablet form is known. However, a solid tablet form may be unsuitable forpatients who have difficulty swallowing, such as children, elderlypatients, stroke patients and/or the like. In order to overcome thisproblem, it would be beneficial to provide a Methotrexate containingcomposition as an oral solution which is palatable, as well asphysically and chemically stable. However, Methotrexate has been foundto precipitate out of solution over time.

BRIEF SUMMARY OF THE INVENTION

It is therefore an aim of the present invention to provide an optimisedMethotrexate composition suitable for oral administration whichovercomes the abovementioned problems.

It is a further aim of the present invention to provide a method ofmanufacturing an improved Methotrexate composition suitable for oraladministration.

It is a yet further aim of the present invention to provide a method ofuse of an improved Methotrexate composition for oral administration.

According to a first aspect of the present invention there is provided aMethotrexate composition suitable for oral administration, saidcomposition containing a pharmaceutically acceptable salt ofMethotrexate and an aqueous carrier agent in which the Methotrexate saltis substantially or completely soluble to form an aqueous solution.

The Methotrexate solution as described herein is stable in that itremains substantially or wholly dissolved in the aqueous agent for aprolonged or predetermined period of time. The term “solution” is incontrast to a Methotrexate containing “suspension” wherein theMethotrexate salt is un-dissolved and homogenously dispersed in asuspension medium.

Any pharmaceutically acceptable soluble salt of Methotrexate can beused. Preferably the pharmaceutically acceptable soluble salt ofMethotrexate used is Methotrexate disodium. This salt is preferably in apowder form prior to addition to the aqueous carrier agent.

Preferably the pH of the composition is within the pH range of 6-7. Ithas been found by the Applicants that at pH values below 6.0 theMethotrexate is seen to precipitate out of solution over time and thelower the pH the greater the amount of precipitate seen. At pH valuesabove 7.0 there is an increase in degradation that will limit the shelflife of the composition.

Further preferably the pH of the composition is within the pH range of6.1-6.5. Yet further preferably the pH of the composition is at pH6.25+/−0.15.

Preferably the aqueous carrier agent is or includes water, purifiedwater and/or the like.

Preferably the composition includes one or more buffer agents or pHmodifying agents to adjust the pH to the preferred range. Thecombination of the pH range used and the buffer strength of the one ormore buffer agents typically prevent precipitation of the Methotrexateand maintain the composition as a substantially clear solution.

The one or more buffer agents can include any or any combination ofCitric Acid, Sodium Citrate, Sodium Dihydrogen Phosphate, DisodiumHydrogen Phosphate, Trometamol (Tris), Hydrochloric Acid, Ascorbic Acid,Sodium Ascorbate, any of the abovementioned sodium salts replaced withpotassium salts and/or the like.

Preferably two or more buffer agents are provided to form a buffersystem, such as a Citric Acid-Sodium Citrate Buffer, Sodium DihydrogenPhosphate-Disodium Hydrogen Phosphate Buffer, Trometamol(Tris)-Hydrochloric Acid Buffer, Trometamol (Tris)-Citric Acid Buffer,Ascorbic Acid-Sodium Ascorbate Buffer, any of the abovementioned sodiumsalts replaced with potassium salts and/or the like.

In a preferred embodiment the two or more buffer agents include citricacid monohydrate and disodium hydrogen phosphate.

Preferably the resulting buffer strength used is in the range of 2millimolar to 200 millimolar. Further preferably the resulting bufferstrength used is in the range of 2-20 millimolar to maximise thestability of the Methotrexate and shelf life of the oral solutionproduct.

Preferably the composition includes one or more preserving agents toincrease the shelf life of the composition. The one or more preservingagents could include any or any combination of Sodium MethylHydroxybenzoate, Sodium Ethyl Hydroxybenzoate, Sodium PropylHydroxybenzoate, Sodium Benzoate, Potassium Sorbate and/or the like.

Preferably the composition includes one or more flavouring compoundsand/or sweetening agents to mask the taste of the Methotrexate saltcontained therein and/or to make the resulting composition morepalatable. The one or more flavouring compounds and/or sweetening agentscan include Sucralose, Acesulfame K, any other water soluble sweetener,Raspberry Flavour 545742E and/or the like that is/are compatible withthe Methotrexate salt used in the composition.

In one embodiment the Methotrexate composition can be used in thetreatment of or for the manufacture of a medicament for the treatment ofany or any combination of a folic acid antagonist, an anti-neoplasticagent, an immunosuppressant, an anti-metabolite, neoplastic disease,malignant disease, psoriasis, Crohn's disease, rheumatoid arthritis,polyarthritic forms of active juvenile idiopathic arthritis, juveniledermatomyositis, vasculitis, uvenlitis, systemic lupus erythematosus,localised scleroderma and sarcoidrosis.

Preferably the pharmaceutically acceptable dosage of the Methotrexatesalt used in the composition is 2.5 mg/5 ml, 5 mg/5 ml, 10 mg/5 ml or inthe range of 0.05 mg/1 ml to 20 mg/1 ml.

In a preferred embodiment the composition includes a pharmaceuticallyacceptable salt of Methotrexate, one or more buffering agents, one ormore preserving agents, one or more sweetener agents and one or moreflavourings.

According to a second aspect of the present invention there is provideda method of manufacturing a Methotrexate composition suitable for oraladministration, said method including the step of mixing apharmaceutically acceptable salt of Methotrexate with an aqueous carrieragent until the Methotrexate salt is substantially or completelydissolved in the carrier agent to form an aqueous solution.

Preferably the method of manufacture takes place at room temperature(i.e. between 18-24° C.) and pressure.

The composition can be mixed together using any suitable mixing means.

Storage temperature of the resulting composition is also typicallyimportant in the stability of said composition. Preferably the storagetemperature of the resulting composition should be at approx. roomtemperature or within the temperature range of 18−25° C.

According to a further aspect of the present invention there is provideduse of a Methotrexate composition in the manufacture of a medicament forthe treatment in a patient as a folic acid antagonist, as ananti-neoplastic agent, an immunosuppressant, an anti-metabolite,neoplastic disease, malignant disease, psoriasis, Crohn's disease,rheumatoid arthritis, polyarthritic forms of active juvenile idiopathicarthritis, juvenile dermatomyositis, vasculitis, uvenlitis, systemiclupus erythematosus, localised scleroderma and/or sarcoidrosis, saidcomposition containing a pharmaceutically acceptable salt ofMethotrexate and an aqueous carrier agent in which the Methotrexate saltis substantially or completely soluble to form an aqueous solution

Preferably the patient is a human patient.

Thus, the present invention provides a pharmaceutically effective, safeand simple to administer oral dosage form (i.e. oral solution) ofMethotrexate that has an increased shelf life and which will benefit apatient group that has problems in swallowing.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graph showing results of analysis of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Detailed embodiments of the present invention will now be described.

Test 1

The Applicants initially undertook a study to calculate the pH at whicha Methotrexate composition containing 10 mg/5 ml Methotrexate Disodiumremained stable (i.e. showed little or no pH drift over time) and thebuffering conditions that provided this stability. The samples in test 1included Batch A which had the pH adjusted to pH 6 and includedbuffering agents; Batch B which had been adjusted to pH 6 but containedno buffering agents; and Batch C which had the pH adjusted to 7 andincluded buffering agents.

More particularly, Batch A included 250 ml of purified water, 5.72 g ofDisodium Hydrogen Phosphate Dihydrate, 1.88 g of Citric AcidMonohydrate, 1.096 g* of Methotrexate Disodium and the formulation wasmade up to 500 ml in purified water. (*Methotrexate Disodium amountincludes a QS calculation to account for the sodium salt and rawmaterial water content to produce 10 mg/5 ml of Methotrexate base in theproduct). The pH was adjusted to pH 6.0 using 10% Citric Acid solution.

Batch B included 250 ml of purified water, 1.096 g* of MethotrexateDisodium and the formulation was made up to 500 ml in purified water.(*Methotrexate Disodium amount includes a QS calculation to account forthe sodium salt and raw material water content to produce 10 mg/5 ml ofMethotrexate base in the product). The pH was adjusted to pH 6.0 using10% Citric Acid solution.

Batch C included 250 ml of purified water, 7.76 g of Disodium HydrogenPhosphate Dihydrate, 0.68 g of Citric Acid Monohydrate, 1.096 g* ofMethotrexate Disodium and the formulation was made up to 500 ml inpurified water. (*Methotrexate Disodium amount includes a QS calculationto account for the sodium salt and raw material water content to produce10 mg/5 ml of Methotrexate base in the product). The pH was adjusted topH 7.0 using 10% Citric Acid solution.

Initially the temperature of the compositions was maintained at 25° C.and the pH was measured at the starting point (t=0), at week 2, week 4and week 8. The results are shown in Table 1 below.

TABLE 1 Time-weeks Batch Variables Condition 0 2 4 8 A pH 6 Buffered 25°C. pH 5.98 pH 6.09 pH 6.15 pH 6.18 B pH 6 25° C. pH 6.36 pH 6.51 pH 6.59pH 7.22 Unbuffered C pH 7.0 25° C. pH 6.93 pH 7.02 pH 7.10 pH 7.17Buffered

NB: At the time of manufacture the pH of both the pH 6 buffered and pH 6unbuffered formulations were adjusted to pH 6.00.

Firstly, the results show the instability of the pH of the compositionwhen no buffering agents are used, based on the fact that at T=0 theunbuffered solution of Batch B had already increased to pH 6.36. Thissuggests that the pH of the Methotrexate solution drifted upwards in theshort time between the end of manufacture of the composition and thetesting of the samples.

The results from test 1 show that the buffered pH 6.0 and pH 7.0formulations had minimal pH drift during the study. The unbuffered pH6.0 formulation showed a marked increase in pH during the study. Thistest demonstrated that the Methotrexate formulation required a buffersystem to control pH drift and to stabilise the resulting composition.

Test 2

The next test was undertaken to determine what effect a buffering systemhad on the levels of degradants present in a 10 mg/5 ml Methotrexatesolution over time. The % of a known degradant (Impurirty E) wasmeasured using an HLPC assay. The same batch samples were made up as fortest 1 and the conditions were maintained at 25° C. The % of degradationwas measured at the start point (T=0), week 2, week 4 and week 8. Theresults are shown in Table 2 below.

TABLE 2 Time-weeks Batch Variables Condition 0 2 4 8 A pH 6 Buffered 25°C. 0.00% 0.00% 0.00% 0.13% B pH 6 25° C. 0.02% 0.10% 0.16% 0.68%Unbuffered C pH 7.0 25° C. 0.00% 0.12% 0.19% 1.80% Buffered

The results show that even after 8 weeks, the levels of degradation inthe Buffered pH 6 formulation remain low throughout the trial with only0.13% for the 25° C. sample with a corresponding pH of 6.18.

The unbuffered pH 6 formulation showed a much higher level ofdegradation of 0.68% at a corresponding pH of 7.22.

This data also showed that without a buffer the Methotrexate 10 mg/5 mlformulation showed a tendency for the pH to drift upwards. However, ifthe pH drifts up to pH 7 or above, the level of the degradationincreases rapidly which will limit the shelf-life of the product.

Therefore, it was concluded that it was preferable to use a buffersystem in the formulation to obtain a level of stability sufficient forobtaining a prolonged shelf life of the product. In order to choose asuitable buffer system and to calculate the desired buffer strength, abuffer was chosen and comprised an 87 millimolar Citric Acid/DisodiumHydrogen phosphate buffer system. The initial formulation tried was asfollows:

Example 1

Ingredient Weight/5 ml Purified Water (A) 3 ml Methotrexate Disodium QSto 10.97 mg Sodium Methyl Hydroxybenzoate QS to 4.80 mg Sodium EthylHydroxybenzoate QS to 2.40 mg Citric Acid Monohydrate 25.0 mg DisodiumHydrogen 57.2 mg Phosphate Dihydrate Sucralose 2.5 mg Raspberry Flavour545742E 10.0 mg Purified Water (C) To 5 ml QS—Quantum Satis (as much asis required to make up the required volume/ weight).

However, on storage a yellow precipitate was seen which was identifiedas Methotrexate. Therefore further investigation work was carried out totry to identify the causative factors of the precipitate and resolvethem.

Batches were prepared at various pHs in the range 5.6-6.0 and wereprepared at ½, 1/10^(th) and 1/20^(th) the original buffer strength ofexample 1 (i.e. the citric acid monohydrate and disodium hydrogenphosphate dihydrate buffer system). The original buffer strength wastaken from a citrate-phosphate buffer table(http://microscopy.berkeley.edu/Resources/instruction/buffers.html).

Visual observations showed that both the pH and ionic strength of thebuffer affected the rate of precipitation of the Methotrexate (i.e. thepoint in time at which precipitation is seen) and the amount ofMethotrexate precipitate produced.

The graph in FIG. 1 shows the results of the analysis of the filteredsupernatant solution for the above Methotrexate formulation at ½ and1/10^(th) original buffer strength at four different pH values; 5.6,5.7, 5.8 and 5.9. The analysis is based on the fact that the lower the %of Methotrexate found in the supernatant (i.e. Assay % SA), the lowerthe amount of Methotrexate remains in solution i.e. fully dissolved.Samples of the supernatant above the precipitate were filtered through aWhatman No. 4 Filter Paper and was assayed using HPLC for theMethotrexate active component.

The results show that by increasing the pH of the formulation towards pH6.0, this increases the amount of Methotrexate dissolved in theformulation. The results also show that there is less Methotrexatedissolved when a ½ strength buffer system is used compared to theformulation using a 1/10^(th) strength buffer system. This in turnsuggests that the Methotrexate composition of the present invention ismore physically stable at a lower ionic buffer strength i.e. does notprecipitate out of solution.

This analytical work is backed up by stability studies which are shownin Table 3 below. The stability studies were undertaken using theexample 1 formulation but using either a citrate-phosphate buffer systemat half the strength (i.e. 43 mmol) or 1/10^(th) of the strength (i.e.8.7 mmol) compared to that of example 1. The formulations were adjustedto 5 different pH values; 5.6, 5.7, 5.8, 5.9 and 6.0. One set offormulations were stored at 5° C. and one set of formulations werestored at 25° C. for each buffer strength and each pH value for theduration of the study. The study took place over a 6 month time period.

TABLE 3 ½ Buffer strength 1/10^(th) Buffer Strength (43 mmol) (8.7 mmol)pH 5° C. 25° C. 5° C. 25° C. 5.6. PPT @ PPT @ PPT @ PPT @ 1 M 1 M 1 M 1M 5.7 PPT @ PPT @ PPT @ PPT @ 1 M 1 M 1 M 1 M 5.8 PPT @ PPT @ PPT @ PPT@ 1 M 1 M 1 M 1 M 5.9 PPT @ PPT @ PPT @ PPT @ 1 M 1 M 1 M 5 M 6.0 CS @CS @ CS @ CS @ 6 M 6 M 6 M 6 M PPT—precipitate observed CS—ClearSolution. No precipitate 1 M represents 1 month time period 5 Mrepresents 5 month time period 6 M represents 6 month time period

The results show that visually there was a increase in the amount ofMethotrexate in solution as the pH in the formulations increased from5.6 to 5.9.

Table 4 shows the results of a similar test undertaken using a standardformulation with different ionic strengths of a citrate-phosphate bufferused and all the formulations adjusted to pH 6.0. One set offormulations were kept at 5° C. and one set of formulations were kept at25° C. for the duration of the study.

Each formulation included 300 g Purified Water, 0.571 g of Sodium MethylHydroxybenzoate (equivalent of 0.96 g/L free acid), 0.281 g of SodiumEthyl Hydroxybenzoate (equivalent to 0.48 g/L free acid), 0.25 gSucralose, 1 g of Raspberry flavour, 1.293 g Methotrexate Disodium (QSto 2.194 g/L) and made up to 500 ml using Purified Water.

The Citrate-Phosphate control had 5.72 g Disodium Hydrogen PhosphateDihydrate and 2.50 g of Citric Acid Monohydrate. The Citrate-Phosphate ½strength buffer had 2.86 g Disodium Hydrogen Phosphate Dihydrate and1.25 g of Citric Acid Monohydrate. The Citrate-Phosphate 1/10^(th)strength buffer had 0.572 g Disodium Hydrogen Phosphate Dihydrate and0.250 g of Citric Acid Monohydrate. The Citrate-Phosphate 1/20^(th)strength buffer had 0.286 g Disodium Hydrogen Phosphate Dihydrate and0.125 g of Citric Acid Monohydrate.

TABLE 4 Buffer Strength Test 5° C. 25° C. Citrate- 87 mmol AppearancePPT @ 2 M PPT @ 6 M Phosphate Degradant NT 0.97% @ 5 M (Control)(Impurity C) Citrate- 43 mmol Appearance PPT @ 3 M CS @ 6 M PhosphateDegradant NT 0.85% @ 5 M (½ strength) (Impurity C) Citrate- 8.7 mmolAppearance CS @ 6 M CS @ 6 M Phosphate Degradant NT 0.76% @ 5 M ( 1/10strength) (Impurity C) Citrate- 4.3 mmol Appearance CS @ 6 M CS @ 6 MPhosphate Degradant NT 0.70% @ 5 M ( 1/20 strength) (Impurity C) NT—NotTested PPT—precipitate observed CS—Clear Solution. No precipitate 2 Mrepresents 2 month time period 3 M represents 3 month time period 6 Mrepresents 6 month time period

The results in Table 4 show that the lower the ionic strength of thecitrate phosphate buffer, the more stable the formulation is at pH 6.0.No precipitate is observed at a buffer strength of mmol on storage at 5°C. There is also a decrease in the amount of degradation observed(impurity C) as the buffer strength is decreased.

Table 5 shows a similar test to that undertaken for Table 4 but aseparate phosphate and citrate buffers were used.

The formulation of the phosphate buffer used in each sample included 180g Purified Water, 0.3426 g of Sodium Methyl Hydroxybenzoate *1(equivalent of 0.96 g/L free acid), 0.1686 g of Sodium EthylHydroxybenzoate *1 (equivalent to 0.48 g/L free acid), 0.15 g Sucralose,0.6 g of Raspberry flavour, 0.7758 g of Methotrexate Disodium (QS to2.194 g/L) and made up to 300 ml using Purified Water.

In the 66 mmol phosphate buffer the formulation included 0.357 g ofDisodium Hydrogen Phosphate Dihydrate and 2.82 g of Sodium DihydrogenPhosphate Dihydrate. In the 33 mmol phosphate buffer the formulationincluded 0.1785 g of Disodium Hydrogen Phosphate Dihydrate and 1.41 g ofSodium Dihydrogen Phosphate Dihydrate. In the 6.6 mmol phosphate bufferthe formulation included 0.0357 g of Disodium Hydrogen PhosphateDihydrate and 0.282 g of Sodium Dihydrogen Phosphate Dihydrate. In the3.3 mmol phosphate buffer the formulation included 0.0182 g of DisodiumHydrogen Phosphate Dihydrate and 0.141 g of Sodium Dihydrogen PhosphateDihydrate.

The formulation of the citrate buffer used in each sample included 600 gPurified Water, 1.141 g of Sodium Methyl Hydroxybenzoate *1 (equivalentof 0.96 g/L free acid), 0.563 g of Sodium Ethyl Hydroxybenzoate *1(equivalent to 0.48 g/L free acid), 0.50 g Sucralose, 2.0 g of RaspberryFlavour, 2.520 g of Methotrexate Disodium (QS to 2.194 g/L) and made upto 1000 ml using Purified Water.

In the 100 mmol citrate buffer the formulation included 25.7 g of SodiumCitrate and 2.65 g of Citric Acid Monohydrate. In the 4.3 mmol citratebuffer the formulation included 1.18 g of Sodium Citrate and 0.1155 g ofCitric Acid Monohydrate.

TABLE 5 Buffer Strength 5° C. 25° c. Phosphate 66 mmol PPT @ 2 M PPT @ 2M Phosphate 33 mmol PPT @ 2 M CS @ 3 M Phosphate 6.6 mmol CS @ 3 M CS @3 M Phosphate 3.3 mmol CS @ 3 M CS @ 3 M Citrate 87 mmol PPT @ PPT @ 1 M1 week Citrate 8.7 mmol PPT @ 3 M CS @ 4 M PPT—precipitate observedCS—Clear Solution. No precipitate 2 M represents 2 month time period 3 Mrepresents 3 month time period 6 M represents 4 month time period

The results in table 5 support the results in table 4 in that the lowerthe ionic strength of the buffer system used in the formulation at pH6.0, the more stable the Methotrexate formulation was over time.

Example 2 below shows a further Methotrexate formulation according to anembodiment of the present invention.

Example 2

Ingredient Specification Weight/5 ml Weight/litre Purified Water (A) Ph.Eur 3 ml 600.00 g Sodium Methyl Ph. Eur QS to 4.80 mg QS to 0.96 gHydroxybenzoate Free acid free acid Sodium Ethyl Ph. Eur QS to 2.40 mgQS to 0.48 g Hydroxybenzoate free acid free acid Disodium Hydrogen Ph.Eur 5.72 mg 1.144 g Phosphate Dihydrate Citric Acid Ph. Eur 6.27 mg1.254 g Monohydrate Raspberry HSE 10.0 mg 2.00 g Flavour 545742ESucralose USP 2.5 mg 500.00 mg Purified water Ph. Eur 0.375 ml 75.00 g(B) Methotrexate Ph. Eur QS to 10.97 mg QS to 2.194 g Disodium(equivalent to 10 mg/5 ml Methotrexate base) Disodium Hydrogen HSE QS topH QS to pH Phosphate Dihydrate (as a 10%^(w)/_(v) solution) Citric AcidHSE QS to pH QS to pH Monohydrate (as a 10%^(w)/_(v) solution) PurifiedWater Ph. Eur To 5 ml To 1000 ml (C) (1010.0 g*)g *based on weight perml of 1.010 g/ml) Ph. Eur—European Pharmacopoeia HSE—In House StandardUSP—United States Pharmacopoeia QS—Quantum Satis (Methotrexate Disodiumand the Sodium p- Hydroxybenzoate preservatives are hygroscopic,therefore will require QS calculations prior to dispensing and batchmanufacture.)

An example method of manufacture is set out below for the formulationshown in example 2. This method is typically undertaken at roomtemperature and pressure and could be carried out using a propellermixer or a high shear mixer for example.

Manufacturing Process

-   1. Add the aqueous carrier agent in the form of Purified Water (A)    to the main manufacturing vessel.-   2. Add the preservatives in the form of Sodium Methylhydroxybenzoate    and Sodium Ethyl Hydroxybenzoate to the main vessel and mix until    substantially dissolved using a suitable mixer.-   3. Add the buffer agent Disodium Hydrogen Phosphate Dihydrate to the    main vessel and mix until substantially dissolved using a suitable    mixer.-   4. Add the buffer agent Citric Acid Monohydrate to the main vessel    and mix until substantially dissolved using a suitable mixer.-   5. Add the flavouring agent in the form of Raspberry Flavour to the    main vessel and mix until substantially dispersed using a suitable    mixer.-   6. Add the sweetening agent in the form of Sucralose to the main    vessel and mix until substantially dissolved using a suitable mixer.-   7. Into a suitable clean separate stage vessel dispense aqueous    carrier agent in the form of purified water (B).-   8. Add the Methotrexate Disodium salt into the separate stage vessel    and mix until substantially dissolved either by hand or using a    suitable mixer.-   9. Add the separate stage Methotrexate solution (from stage 8) into    the main vessel and mix until substantially dispersed using a    suitable mixer.-   10. Check the pH. If it is outside the range of 6.25+/−0.15 adjust    the pH until it is within this range by using either 10% w/v    solution of Citric Acid Monohydrate to lower the pH or a 10% w/v    solution of Disodium Hydrogen Phosphate Dihydrate to increase the    pH.-   11. Add Purified Water (C) to make to final weight and mix until    substantially dispersed using a suitable mixer.-   12. The finished product is filled into amber glass bottles.

While the invention has been described with a certain degree ofparticularity, it is manifest that many changes may be made in thedetails of construction and the arrangement of components withoutdeparting from the spirit and scope of this disclosure. It is understoodthat the invention is not limited to the embodiments set forth hereinfor purposes of exemplification, but is limited only by the scope of theattached claims, including the full range of equivalency to which eachelement thereof is entitled.

1. A Methotrexate composition for oral administration, said compositioncontaining a pharmaceutically acceptable salt of Methotrexate and anaqueous carrier agent in which the Methotrexate salt is substantially orcompletely soluble to form an aqueous solution.
 2. The Methotrexatecomposition according to claim 1 wherein the pharmaceutically acceptablesalt of Methotrexate used is Methotrexate disodium.
 3. The Methotrexatecomposition according to claim 1 wherein the pH of the composition is inthe range of pH 6-7.
 4. The Methotrexate composition according to claim3 wherein the pH of the composition is in the range pH 6.1-6.5.
 5. TheMethotrexate composition according to claim 4 wherein the pH of thecomposition is in the range pH 6.25+/−0.15.
 6. The Methotrexatecomposition according to claim 1 wherein the aqueous carrier agentcomprises or includes water or purified water.
 7. The Methotrexatecomposition according to claim 1 wherein the composition comprises orincludes one or more buffer agents or pH modifying agents to adjust thepH to the preferred range.
 8. The Methotrexate composition according toclaim 7 wherein the one or more buffer agent or pH modifying agentscomprise or include any or any combination of Citric Acid, Citric AcidMonohydrate, Sodium Citrate, Sodium Dihydrogen Phosphate, DisodiumHydrogen Phosphate, Trometamol (Tris), Hydrochloric Acid, Ascorbic Acid,Sodium Ascorbate, any of the abovementioned sodium salts replaced withpotassium salts.
 9. The Methotrexate composition according to claim 1wherein the composition comprises two or more buffer agents to form abuffer system.
 10. The Methotrexate composition according to claim 9wherein the two or more buffer agents are any of a Citric Acid-SodiumCitrate Buffer, Citric Acid Monohydrate-Disodium Dihydrogen Phosphate,Sodium Dihydrogen Phosphate-Disodium Hydrogen Phosphate Buffer,Trometamol (Tris)-Hydrochloric Acid Buffer, Trometamol (Tris)-CitricAcid Buffer, Ascorbic Acid-Sodium Ascorbate Buffer, any of theabovementioned sodium salts replaced with potassium salts.
 11. TheMethotrexate composition according to claim 9 wherein the two or morebuffer agents include Citric acid monohydrate and Disodium hydrogenphosphate.
 12. The Methotrexate composition according to claim 7 whereinthe buffer strength used is between 2 to 200 millimolar, and optionallybetween 2 to 20 millimolar.
 13. The Methotrexate composition accordingto claim 1 wherein the composition comprises or includes one or morepreserving agents.
 14. The Methotrexate composition according to claim13 wherein said preserving agent or agents comprise or include any orany combination of Sodium Methyl Hydroxybenzoate, Sodium EthylHydroxybenzoate, Sodium Propyl Hydroxybenzoate, Sodium Benzoate orPotassium Sorbate.
 15. The Methotrexate composition according to claim 1wherein the composition comprises one or more flavouring compoundsand/or sweetening agents.
 16. The Methotrexate composition according toclaim 15 wherein the one or more flavouring compounds and/or sweeteningagents comprises or includes Sucralose, Acesulfame K, any other watersoluble sweetener or Raspberry Flavour 545742E.
 17. The Methotrexatecomposition according to claim 1 wherein the pharmaceutically acceptabledosage of the Methotrexate salt used is 2.5 mg/5 ml, 5 mg/5 ml, 10 mg/5ml or in the range of 0.05 mg/1 ml to 20 mg/1 ml.
 18. A method ofmanufacturing a Methotrexate composition for oral administration, saidmethod including the steps of mixing a pharmaceutically acceptable saltof Methotrexate with an aqueous carrier agent until the Methotrexatesalt is substantially or completely soluble in the carrier agent to forman aqueous solution.
 19. A method according to claim 14 wherein saidmethod takes place at room temperature (between 18-24° C.) and pressure.20. A Methotrexate composition for use as a folic acid antagonist, as ananti-neoplastic agent, an immunosuppressant, an anti-metabolite, or foruse in the treatment of neoplastic disease, malignant disease,psoriasis, Crohn's disease, rheumatoid arthritis, polyarthritic forms ofactive juvenile idiopathic arthritis, juvenile dermatomyositis,vasculitis, uvenlitis, systemic lupus erythematosus, localisedscleroderma and sarcoidrosis.
 21. A Methotrexate composition for useaccording to claim 20 wherein said composition contains apharmaceutically acceptable salt of Methotrexate and an aqueous carrieragent in which the Methotrexate salt is substantially or completelysoluble to form an aqueous solution.
 22. A Methotrexate composition foruse according to claim 20 wherein said composition includes one or morebuffering agents, one or more preserving agents, one or more sweeteneragents and one or more flavourings.